A natural sugar called trehalose blocks glucose from the liver and activates a gene that boosts insulin sensitivity, which reduces the chance of developing diabetes, according to new research in mice.

Activating the gene also triggers an increase in burned calories, reduces fat accumulation and weight gain, and lessens measures of fats and cholesterol in the blood.

The findings suggest new possibilities for treating metabolic syndrome, a cluster of related conditions that includes obesity, diabetes, and fatty liver disease.

“…fasting—or giving trehalose with a normal diet—triggers the liver to change the way it processes nutrients, in a beneficial way.”

While potential medicinal use of trehalose still requires considerable research, the investigators found that giving mice trehalose via drinking water resulted in beneficial effects on the animals’ liver metabolism—similar to benefits that resulted from fasting. In fasting mice, the liver also turns on the same gene that improves the body’s ability to use insulin.

“We learned that this gene, Aloxe3, improves insulin sensitivity in the same way that common diabetes drugs—called thiazolidinediones—improve insulin sensitivity,” says Brian DeBosch, an assistant professor of pediatrics at Washington University in St. Louis. “And we showed that Aloxe3 activation in the liver is triggered by both trehalose and by fasting, possibly for the same reason: depriving the liver of glucose.

Mice that eat a diet high in trans fats and cholesterol for 12 weeks show fatty deposits in the liver (red staining). The new study shows that the natural sugar trehalose blocks glucose from getting into the liver and turns on a gene, Aloxe3, that improves insulin sensitivity and other measures of metabolic syndrome, including reducing such fatty liver deposits. (Credit: Brian DeBosch via Washington U.)

“In mice, this gene is turned on as part of what seems to be the normal fasting response. Our data suggest that fasting—or giving trehalose with a normal diet—triggers the liver to change the way it processes nutrients, in a beneficial way. And if glucose can be blocked from the liver with a drug, it may be possible to reap the benefits of fasting without strictly limiting food.”

The researchers found that Aloxe3 in the liver—whether fasting or trehalose activated it—leads the mice not only to make better use of insulin, but to increase calorie burning, raise body temperature, reduce weight gain and fat accumulation—including fat deposits in the liver—and lessen measures of fats and cholesterol in the blood.

Further, they found that mice that eat an obesity-inducing diet and mice that eat freely and are genetically prone to obesity didn’t develop metabolic disease if they received trehalose via their drinking water.

Mice that eat a typical chow diet show a healthy liver (left panel). Mice eating a high-trans-fat, high-cholesterol diet for 12 weeks show large fatty deposits in the liver (red staining in middle panel). Mice that eat the same high-trans-fat, high-cholesterol diet and that have the gene Aloxe3 turned on at high levels show smaller fatty deposits, suggesting protection from metabolic syndrome. (Credit: Brian DeBosch via Washington U.)

Studying the genes switched on in the livers of mice given trehalose, DeBosch and his colleagues became intrigued by Aloxe3, which is typically known for helping the skin maintain proper hydration in the body and had not been thought to have any role in the liver.

The researchers found that activating Aloxe3 in the mice given trehalose improves insulin sensitivity in a way that is similar to how thiazolidinediones work. Studying healthy mice given only water over a 48-hour period, they found that fasting, likewise, activates Aloxe3 in the liver. This activation could boost insulin sensitivity in the same way.

However, DeBosch says, trehalose may encounter enzymes in the digestive tract that break it apart, releasing its two glucose molecules, which would be counterproductive. The researchers investigated a similar sugar—lactotrehalose—they found has the same beneficial effects from triggering Aloxe3 but does not break apart as easily.

The Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program, supported the work. The National Institutes of Health (NIH); the Children’s Discovery Institute; the AGA-Gilead Sciences Research Scholar Award in Liver Disease; the Robert Wood Johnson Foundation; the Washington University Spencer T. Olin Fellowship; and National Science Foundation Graduate Student Fellowship also supported the work. Herbert Virgin and David Rudnick provided specific mouse strains.